Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs-University, Freiburg, Germany.
PLoS One. 2013 Apr 9;8(4):e60679. doi: 10.1371/journal.pone.0060679. Print 2013.
P-glycoprotein is capable of effluxing a broad range of cytosolic and membrane penetrating xenobiotic substrates, thus leading to multi-drug resistance and posing a threat for the therapeutic treatment of several diseases, including cancer and central nervous disorders. Herein, a virtual screening campaign followed by experimental validation in Caco-2, MDKCII, and MDKCII mdr1 transfected cell lines has been conducted for the identification of novel phospholipids with P-gp transportation inhibitory activity. Phosphatidylinositol-(1,2-dioctanoyl)-sodium salt (8∶0 PI) was found to significantly inhibit transmembrane P-gp transportation in vitro in a reproducible-, cell line-, and substrate-independent manner. Further tests are needed to determine whether this and other phosphatidylinositols could be co-administered with oral drugs to successfully increase their bioavailability. Moreover, as phosphatidylinositols and phosphoinositides are present in the human diet and are known to play an important role in signal transduction and cell motility, our finding could be of substantial interest for nutrition science as well.
P-糖蛋白能够将广泛的细胞质和膜穿透的外源生物底物排出细胞，从而导致多药耐药，并对包括癌症和中枢神经系统疾病在内的多种疾病的治疗构成威胁。在此，我们进行了一项虚拟筛选活动，并在 Caco-2、MDKCII 和 MDKCII mdr1 转染细胞系中进行了实验验证，以鉴定具有 P-糖蛋白转运抑制活性的新型磷脂。发现磷脂酰肌醇-(1,2-二辛酰基)-钠盐（8∶0 PI）可在体外以可重复、细胞系和底物非依赖性的方式显著抑制跨膜 P-糖蛋白转运。需要进一步的测试来确定这种和其他磷脂酰肌醇是否可以与口服药物共同给药，以成功提高其生物利用度。此外，由于磷脂酰肌醇和磷酸肌醇是人类饮食中的成分，并且已知在信号转导和细胞运动中发挥重要作用，我们的发现可能对营养科学也具有重要意义。
